What’s holding up biosimilar development?


Canada, the E.U., South Korea, Japan, India, and Australia - all have had clear regulatory pathways in place for years. The United States has been working on a biosimilars pathway for almost a decade. What's different?

Regulatory and legal hurdles could threaten the growth of the biosimilars market in the United States unless federal and state governments, and the groups trying to influence them, clarify the rules pertaining to such issues as the naming of biosimilars and their interchangeability with reference biologics.

While the repair of what some have called a “broken” structure may start with changes in how FDA runs its biosimilars program, reforming state regulations and creating a legal climate that’s more welcoming toward developers of biosimilar products also can help move the biosimilars market forward, according to panelists at the Biosimilars 20/20 conference held recently in Philadelphia.

A “broken” approval process?

“We have a dangerously broken regulatory model,” said Gillian Woollett, MA, DPhil, senior vice president for Avalere Health and former vice president of the Pharmaceutical Research and Manufacturers of America (PhRMA). “If the FDA continues to approve at a rate of 11 biologics a year, with nearly 1,000 in development (already in clinical trials), it will take 100 years to get those in the pipeline today approved.”

Developers of biosimilars can take one of three different pathways to FDA approval, Woollett said: the new drug application (NDA) route, which includes an abbreviated NDA as one option; the biologic license application (BLA) or “stand alone” application, known as 351(a); or the distinctive pathway known as 351(k), set up for biosimilars by the Affordable Care Act.

“The FDA is massively emphasizing that the basis of biosimilarity is the analytics that establish similarity, and therefore biosimilarity between the biosimilar product and the reference product,” Woollett said. Biosimilar developers must base their clinical studies confirming the biosimilarity on pharmacokinetics, pharmacodynamics, and immunogenicity.

Late on the scene

Globally, U.S. developers of biologics are in a difficult position, Woollett said.

“The United States is 50% of the global market for biologics but only 5% of the world’s population, so you can see the unsustainability in terms of prices and costs,” she said. “You can see why emerging markets - at 45% of the world’s population - are beginning to have a role.”

But regulatory and legal issues are causing U.S. companies to arrive “late” to the global biosimilars market, Woollett said.

“You could say, if a product is already approved in Europe, why is there a need for additional clinical studies in the United States? That’s a very, very good question, but the difference in products is not in the tube but on the label, and therefore dependent on the legal-regulatory as well as the scientific climate.”

Manufacturer maneuvers

Makers of reference biologics also are influencing the biosimilars regulatory climate.

Steven Miller, MD, MBA, senior vice president of Express Scripts, said that the FDA has changed its approach to approving indications for biosimilars. In March, FDA approved Zarxio for all the indications of its reference biologic, Amgen’s Neupogen - a concept known as full extrapolation.

“But a couple of months later, we no longer have full extrapolation,” he said. “This actually has been ingenious on the part of the originators, and this is now spreading across other molecules.”


Global vs. regional 

Other regulatory hurdles biosimilar developers must face involve the challenge of developing and manufacturing agents for multiple markets and naming standards.

On more regional and national levels, challenges revolve around the differences between health systems, regional regulations that require some harmonization for biosimilars and reference biologics, and varying innovator products.

Even with the 351(k) pathway, the United States is still awaiting a clear regulatory path to market for biosimilars, Miller said. He noted that Canada, the European Union (EU) South Korea, Japan, India, and Australia all have had clear regulatory pathways in place for years, whereas “we’ve been working on a pathway for biosimilars now for almost a decade.”

Conflicting constituencies

Conflicting constituencies have slowed that process, said Miller.

The companies that make reference brand drugs want to protect their patents, while support for biosimilars among patient groups is “weak”- and “patient groups get their funding from the pharmaceutical industry,” he said.

“We’ve got an industry that’s disproportionately afraid of biosimilars, and that industry is now damaging their own arguments that have hurt their ability to get their originator products approved,” Miller said. “The FDA needs to be less political.”

An alternative, Miller said, would be to “go back to MedPAC pre-2009,” meaning the Medicare Payment Advisory Commission, which “dictated” drug prices.

“That’s not going to be good for the originator drugs,” he said. “If we want biosimilars approved, even if we want originator drugs approved, we’ve got to get the FDA to move off this cautious approach, because obviously they are doing nothing.”

Interchangeability and naming

Interchangeability - the ability to allow pharmacies and providers to swap out one biosimilar for another or for the reference biologic, as they do with generics - is one area where FDA needs to clarify its guidance in order for the biosimilars market to move forward, Woollett said. “I wouldn’t hold my breath on it,” she added.

What’s more, individual states either have enacted or are enacting their own regulations on biosimilars, Woollett said. Eight states have already enacted legislation and 10 others are deliberating legislation that has been introduced. In eight other states, legislation is moving toward introduction.

For pharmacies, switching a patient from the reference biologic to a biosimilar would require a new physician’s prescription, Miller said. But Woollett noted that for an FDA-approved biosimilar, the question of interchangeability with the reference biologic is academic.

“If it fails in a study of interchangeability (as opposed to “not proven”), then it’s not a biosimilar in the first place,” she said.


Regulatory issues

For pharmacies, interchangeability can be a state-level regulatory issue, said Thomas Sullivan, president of Rockpointe and editor of the website Policy and Medicine (www.policymed.com).  

“State pharmacy boards are populated by retail pharmacists,” he said. “They do things that are going to be most favorable to their businesses. Pharmacies like to dispense expensive drugs. They think about the spread” - the margin between their cost and the retail price. “Historically, they have not been incentivized to dispense less expensive drugs.” Getting state legislation that’s biosimilar-friendly “is going to be difficult,” he said.

Woollett called the  nonproprietary naming situation for biologics “a complete mess.” And it is not clear whether FDA will issue its promised draft guidance on the nonproprietary naming of all biologics this year, she said.

 “Naming makes a big difference for physicians,” Miller said. “The doctor always writes the prescription to the originator name.”

With generics the substitution process is straightforward, but not so with biosimilars, he said. And while pharmacies need only stock one brand of a generic drug to fill all prescriptions, they would be hard-pressed to stock all the variants of a biosimilar, unless rules on interchangeability are eased.

“We’ve estimated that the naming issue could affect adoption of biosimilars by about a third, which is actually significant when working on these lower-margin products,” he said.

The patent dance

Woollett said that another dynamic complicating the regulatory and legal environment for biosimilars is the so-called “patent dance” provision in the Biologics Price Competition and Innovation Act (BPCIA) of 2009, which set up the existing FDA approvals pathway for biosimilars. The provision was central to Amgen’s attempt to block Sandoz from bringing Zarxio to market, which a U.S. District Court in Northern California threw out.

The patent-dance provision states that a biosimilar applicant “shall” submit its manufacturing information to the maker of the reference drug within 20 days of submitting its application. Sandoz, however, refused, and the court ruled that “shall” does not necessarily mean “must.”

But that provision has given some biosimilar drug sponsors pause, Woollett said.

“Some companies have said outright that if they have to engage in the patent dance, they are not going to file 351(k) applications,” she said. “They will file 351(a) stand-alone applications instead, such as was done for Granix, Teva’s biosimilar filgrastim from Europe.” 

Richard Mark Kirkneris an independent healthcare journalist in Greater Philadelphia.

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